Abstract
Cytokines mediate tight junction defects which contribute to diarrhea in inflammatory bowel diseases (IBD). Diarrhea has been treated in traditional Eastern medicine for a long time by the plant alkaloid berberine. We tested the hypothesis that berberine may have beneficial effects on TNFα-induced paracellular barrier defects. The effects of TNFα and berberine on confluent monolayers of HT-29/B6 human colon cells and on rat colon was analyzed in Ussing chambers in vitro. Localization and regulation of tight junction proteins was analyzed by Western blot and confocal laser scanning microscopy. TNFα caused a marked decrease of barrier properties in HT-29/B6 cells and in rat colon. Molecular analyses revealed a TNFα-induced removal of claudin-1 from the tight junction and an increased claudin-2 expression. Incubation with berberine prevented the TNFα effect. Blocker experiments in combination with phosphoblotting revealed that this effect was mediated via tyrosine kinase, pAkt, and NFκB pathways. Berberine alone inhibited phosphorylation of P42/P44 and phospho P38. TNFα-mediated impairment of paracellular barrier properties can be targeted directly by the plant alkaloid berberine. These results, obtained in colonic cell cultures as well as in colon epithelium, suggest a potential approach for therapeutic intervention in cytokine-mediated inflammatory diseases. (Supported by DFG FOR 721)
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